Bacteria: An Unlikely Source for Cancer Therapy

Akriti Trehan received a Master of Science degree from Georgetown University and currently researches the interface between the microbiome and lung cancer.

Cancer is a disease that affects millions of people across the world. It is caused by abnormal cells in the body that divide uncontrollably; metastasis more specifically describes this uncontrolled cell growth spreading to other parts of the body. Over the years, many novel cancer therapies have been studied and developed including surgical resection, radiotherapy, and chemotherapy. These treatments have been found to be effective for many cancer patients around the world and saved thousands of lives every year. Surgery, radiotherapy, and chemotherapy all carry their own inherent risks and potentially damaging side effects; that’s why a less invasive yet equally powerful treatment against a variety of cancers is a holy grail in oncology. Therefore, researchers are always trying to find other forms of anti-cancer therapy. You’ll see that some seem to come a bit more out of left field than others.

Scientists began to think about the role of bacteria and their potential as anti-cancer agents in the nineteenth century. Researchers noticed certain species of anaerobic (living without a need for oxygen) bacteria that ate up cancerous tissue but died in the presence of normal, oxygen-rich cells. Further investigations found that, more specifically, bacterial spores would travel to oxygen-starved areas in tumor tissue and become actively replicating bacteria upon reaching this destination. Bacterial spores are dormant forms of bacteria that have no metabolic activity and are highly resistant due to harsh environmental conditions. Bacteria known as Clostridia (perhaps you have heard of Clostridium difficile, an intestinal pathogen) were often found to be tumor regressing microbes. This all seemed well and good in theory: infect someone with a strain of anaerobic bacteria and watch them feed on tumors. However, in practice, the proliferation of Clostridia obviously led to acute toxicity and ultimately death in mouse models. The failure to translate laboratory observations into clinical therapy caused bacterial oncology to withdraw into the shadows of radiotherapy and chemotherapy for many years. Why would you infect an already ill person with a pathogen? It seemed ludicrous to many.

Perhaps surprisingly, bacteria cancer therapy was revived later in the twentieth century. The advent of genetic engineering found opportunities to circumvent the potential for serious infections. The use of live, attenuated or genetically-modified, non-pathogenic bacteria emerged as a potential antitumor strategy. Scientists proposed using attenuated bacteria (the way many vaccines today use attenuated viruses) as part of a combination therapy using existing cancer drugs. Since bacterial species alone were not guaranteed to wipe out an entire tumor (how could you force them to act with such specificity?), scientists hypothesized that combining them with chemotherapeutic treatments could increase efficacy. Two stones, one bird. Researchers created an attenuated strain of Clostridium novyi they dubbed C. novyi-NT. This strain was the product of deleting a gene coding for a lethal toxin present in the bacteria. Researchers then performed studies in which they administered this attenuated strain in cancer-ridden mice along with a combination of chemotherapeutic drugs. They called this therapy Combination Bacteriolytic Therapy, or COBALT. COBALT showed significant anti-tumor activity, but not without animal deaths due to toxicity of a foreign microbe.  

Scientists have also examined approaches to use genetically-modified bacteria to express specific anti-cancer genes. By presenting a gene of interest to a tumor micro-environment, bacterial vectors could provide a powerful adjuvant therapy to various cancer treatments. For example, proteins such as Tumor necrosis (quite literally “tumor death”) factor alpha (TNF-α) that regulate immune cells could be cloned and expressed in a microbe known as Clostridium acetobutylicum. Bacteria hence could serve as vehicles to deliver anticancer agents to a cancerous environment. In another example, Bifidobacterium adolescentis bacteria were used as a delivery system in mice for a protein called endostatin, which is known to inhibit tumor growth. Researchers also thought that an attenuated bacterial form of Salmonella typhimurium (the causative agent of typhoid fever) could be used to treat liver cancer. They hypothesized that this anaerobe could be used to deliver chemicals that stimulate the human immune system near the tumor and target the out-of-control cancer cells for destruction.

Another interesting concept in bacterial oncology is known as Directed Enzyme Prodrug Therapy, or DEPT. Enzymes are protein molecules that accelerate chemical reactions and are ubiquitous in living organisms. Reaction substrates (the starting material of a chemical reaction) are quickly converted into products with the help of an enzyme catalyst. In DEPT, an enzyme converts a prodrug (the inactive form of a medication) into the active form of the drug. In this way, a drug only becomes active in the environment it’s supposed to be active in: the tumor. Whereas modern chemotherapeutic drugs lack specificity for cancer sites, DEPT is an experimental method that allows high levels of active drugs to reach a specific, high risk site in the body while leaving healthy cells unperturbed and thus lessening detrimental side effects. So far, DEPT has seen some success in mouse models, but it has a long way to go before entering human trials.

A few weeks ago, we discussed on Infective Perspective the idea that our immune systems have the capability of destroying cancerous cells. This is one of the pillars of the growing field of immunotherapy, and the principle behind it involves stimulating the immune system to destroy the targeted tumor cells. We have written about Duke University researchers who boosted brain tumor treatment by activating patient immune systems with a tetanus shot. To this vein, scientists have tried similarly introducing an attenuated but still invasive form of S. typhimurium. This experiment was found to infect malignant cells and trigger a local immune response, drawing our own immune cells to do the work of fighting off a tumor. This specific therapy successfully treated melanoma cells in the lab. Similarly, introducing bacterial spores triggers an inflammatory response in which the immune system produces chemicals to directly assist the destruction of tumor cells (a lot like the tetanus shot boosting a local immune response in the Duke study).

There are major limitations that accompany the use of bacteria as anti-cancer agents, the biggest being toxicity. It seems that attenuating bacterial harmfulness attenuates its purpose in tumor cells to begin with, which creates a bit of a paradox when considering bacterial cancer treatment. Strategies that remove toxic genes, like COBALT described above, still lead to occasional death in mice, which is concerning for groups trying to push their work into human trials. In addition to toxicity, bacteria are not able to consume all parts of a tumor alone, which is why combination therapies with chemotherapeutic drugs have been studied. This adds to adverse side effects, since chemotherapeutic drugs are notoriously unpleasant.

Cancer is a multifactorial disease: there is no end-all individual therapy. For this reason, scientists have worked on combining other therapies to increase the breadth and effectiveness of such treatments. Certain bacteria tested in mice have shown promising results in targeting invasive tumors, which is an important step in the right direction. The scope of applications of bacteria – often regarded as foes more than friends to our bodies – is astonishing, and we may only be at the surface of it all as there is more to come! In any case, we live in a time where the benefits of bacteria are becoming increasingly apparent, and should only expect to see them play bigger and bigger roles in medicine.

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